Acute High Dose Melatonin for Encephalopathy of the Newborn (ACUMEN):Phase I Study
Lead Research Organisation:
University College London
Department Name: Neonatology
Abstract
Problems around birth leading to a critical lack of oxygen to the baby leads to disordered brain function which can result in brain damage. Over the last 2 decades, doctors have introduced cooling for babies with likely brain damage at birth. Cooling is a safe and effective treatment where a baby's body is cooled by 3 degrees for three days. Cooling improves outcomes, however, despite cooling, many babies still have problems with physical development, learning, behaviour and memory around school age. New therapies to improve outcomes with cooling are urgently needed.
Over the last 10y, several therapies have been studied but, as yet, no therapy apart from cooling exists for these babies. One promising therapy is melatonin, a naturally occurring hormone produced in the brain at night. Melatonin is known to regulate the sleep-wake cycle; at high dose (higher than the body secretes) melatonin "mops-up" damaging chemicals in the circulating blood and stops cells dying. Melatonin is safe and has been used in children at high dose for long periods of years with no side effects. We have shown in animals that adding high doses of melatonin (20mg/kg) to cooling leads to better protection than cooling alone; a loading dose of 20mg/kg is necessary to deliver melatonin as rapidly as possible with brain protection related to achieving high melatonin levels (15-30mg/L) within 6h. Melatonin therefore has the potential to benefit babies. When melatonin is dissolved in a small amount of alcohol, the protection is better. We have spoken to the UK regulatory body, the MHRA, who see the large potential of treatment benefit given this high risk population as long as alcohol is kept below recommended safe levels.
The first milestone of this study is to outsource the manufacture of the melatonin medicine (with alcohol) to a standard we can use in babies. The pharmaceutical company will run tests to ensure the medicine is pure and stable over several months.
In milestone 2, following manufacture of the medicine, we will assess safety of melatonin at 4 dose levels in 25-40 babies at risk of brain injury in the "Dose Escalation Study". We will recruit babies from three large UK hospitals (UCLH, Manchester and Edinburgh) and three large Irish hospitals (Coombe and Rotunda Hospitals in Dublin and Cork) over 12 months.
We will start with one quarter of the estimated effective melatonin dose; this quarter dose will be 5mg/kg loading given within 6h of birth, followed by 2.5mg/kg 12hrly maintenance doses from 24-72h (total of 6 doses). The minimum sample size in the dose escalation study will be 25 babies, with cohorts of 5 babies at each dose level (quarter, half, three quarters and full dose). A safety committee will carefully assess the clinical data, before allowing the next melatonin level to be assessed. Levels of melatonin and ethanol will be measured; these values will be used in the predictive models to inform the safety board of expected levels. Using such models we will avoid blood alcohol levels over the safety limit of 0.25g/L (safety recommendation from the American Academy of Paediatrics 1984).
We will assess "dose limiting events" which include:
1. Severe drop in blood pressure during the melatonin infusion unresponsive to two therapies to improve blood pressure
2. Death
The maximum tolerated dose will be the dose where these events occur in <33% of babies
While waiting for the safety committee, backfilling to a lower safe dose is allowed.
Following the dose escalation study and identification of the recommended dose of melatonin, we will perform a "Cohort expansion Study" for 6 months in the same 6 hospitals plus 2 hospitals in Australia (collaborator sites). This will further confirm safety, feasibility of recruitment, explore consent processes and imaging across sites.
In milestone 3, after data analysis and write up, if results positive, we will pursue funding for a future phase II study of melatonin.
Over the last 10y, several therapies have been studied but, as yet, no therapy apart from cooling exists for these babies. One promising therapy is melatonin, a naturally occurring hormone produced in the brain at night. Melatonin is known to regulate the sleep-wake cycle; at high dose (higher than the body secretes) melatonin "mops-up" damaging chemicals in the circulating blood and stops cells dying. Melatonin is safe and has been used in children at high dose for long periods of years with no side effects. We have shown in animals that adding high doses of melatonin (20mg/kg) to cooling leads to better protection than cooling alone; a loading dose of 20mg/kg is necessary to deliver melatonin as rapidly as possible with brain protection related to achieving high melatonin levels (15-30mg/L) within 6h. Melatonin therefore has the potential to benefit babies. When melatonin is dissolved in a small amount of alcohol, the protection is better. We have spoken to the UK regulatory body, the MHRA, who see the large potential of treatment benefit given this high risk population as long as alcohol is kept below recommended safe levels.
The first milestone of this study is to outsource the manufacture of the melatonin medicine (with alcohol) to a standard we can use in babies. The pharmaceutical company will run tests to ensure the medicine is pure and stable over several months.
In milestone 2, following manufacture of the medicine, we will assess safety of melatonin at 4 dose levels in 25-40 babies at risk of brain injury in the "Dose Escalation Study". We will recruit babies from three large UK hospitals (UCLH, Manchester and Edinburgh) and three large Irish hospitals (Coombe and Rotunda Hospitals in Dublin and Cork) over 12 months.
We will start with one quarter of the estimated effective melatonin dose; this quarter dose will be 5mg/kg loading given within 6h of birth, followed by 2.5mg/kg 12hrly maintenance doses from 24-72h (total of 6 doses). The minimum sample size in the dose escalation study will be 25 babies, with cohorts of 5 babies at each dose level (quarter, half, three quarters and full dose). A safety committee will carefully assess the clinical data, before allowing the next melatonin level to be assessed. Levels of melatonin and ethanol will be measured; these values will be used in the predictive models to inform the safety board of expected levels. Using such models we will avoid blood alcohol levels over the safety limit of 0.25g/L (safety recommendation from the American Academy of Paediatrics 1984).
We will assess "dose limiting events" which include:
1. Severe drop in blood pressure during the melatonin infusion unresponsive to two therapies to improve blood pressure
2. Death
The maximum tolerated dose will be the dose where these events occur in <33% of babies
While waiting for the safety committee, backfilling to a lower safe dose is allowed.
Following the dose escalation study and identification of the recommended dose of melatonin, we will perform a "Cohort expansion Study" for 6 months in the same 6 hospitals plus 2 hospitals in Australia (collaborator sites). This will further confirm safety, feasibility of recruitment, explore consent processes and imaging across sites.
In milestone 3, after data analysis and write up, if results positive, we will pursue funding for a future phase II study of melatonin.
Technical Summary
Despite treatment with therapeutic hypothermia (HT) in developed countries, only 60% of babies with neonatal encephalopathy (NE) survive without cerebral palsy or neurocognitive impairment, with important societal consequences. Novel adjunct therapies are needed. Melatonin (MEL) is a safe and powerful antioxidant with robust brain protection at pharmacological levels in preclinical models (rodent, lamb, piglet) as a single agent and combined with HT; the standardised mean difference (SMD) of combined outcomes (infarct size, neurobehavioural outcome, cell death) on meta-analysis is -0.92, 95% CI (-1.26 to -0.58).
In vitro and efficacy studies suggest a concentration dependent reduction in cell death with MEL and need for early dosing. MEL with ethanol excipient is more beneficial than non-ethanol formulations (SMD -1.14, 95% CI (-1.64 to -0.65)). The aims of this phase I study are:
(i) GMP production of MEL formulation, fill-finish, QP release.
(ii) A dose escalation study of MEL in term babies with moderate-severe NE in six tertiary neonatal centres (UK, Ireland) over 12 mo. In piglet studies MEL therapeutic levels (15-30mg/L) are achieved with 20mg/kg MEL infused intravenously over 2h, followed by 10mg/kg 12hrly from 24h. We will assess PK and dose limiting events (DLE) of ¼ , ½ , ¾ and full dose in 24-39 babies with HT (3 babies per cohort, PK obtained before second dose for the 1st baby at each dose level). DSMB will assess DLEs (defined as severe hypotension and/or death) and graded AEs. Escalation with overdose control will be used to determine the maximum tolerated dose (MTD) achieving median blood MEL between 15-30mg/L and ethanol <0.25g/L (FDA guide). The recommended phase II dose (RP2D) will be either the MTD or lower, depending on PK-dose relationship.
(iii) A cohort expansion for 6mo in 8 centres (2 Australian sites), in 20 babies given the RP2D to confirm safety, recruitment feasibility, PK and cross-site harmonisation of MRI/MRS imaging biomarkers
In vitro and efficacy studies suggest a concentration dependent reduction in cell death with MEL and need for early dosing. MEL with ethanol excipient is more beneficial than non-ethanol formulations (SMD -1.14, 95% CI (-1.64 to -0.65)). The aims of this phase I study are:
(i) GMP production of MEL formulation, fill-finish, QP release.
(ii) A dose escalation study of MEL in term babies with moderate-severe NE in six tertiary neonatal centres (UK, Ireland) over 12 mo. In piglet studies MEL therapeutic levels (15-30mg/L) are achieved with 20mg/kg MEL infused intravenously over 2h, followed by 10mg/kg 12hrly from 24h. We will assess PK and dose limiting events (DLE) of ¼ , ½ , ¾ and full dose in 24-39 babies with HT (3 babies per cohort, PK obtained before second dose for the 1st baby at each dose level). DSMB will assess DLEs (defined as severe hypotension and/or death) and graded AEs. Escalation with overdose control will be used to determine the maximum tolerated dose (MTD) achieving median blood MEL between 15-30mg/L and ethanol <0.25g/L (FDA guide). The recommended phase II dose (RP2D) will be either the MTD or lower, depending on PK-dose relationship.
(iii) A cohort expansion for 6mo in 8 centres (2 Australian sites), in 20 babies given the RP2D to confirm safety, recruitment feasibility, PK and cross-site harmonisation of MRI/MRS imaging biomarkers
